SGLT2 and SGLT1: what is the difference?

Diabetes stays a really complex disease to oversee medically, requiring insulin for type 1 diabetes (T1DM) and lifestyle changes equivalent to food plan, exercise, and weight reduction, together with oral or injectable antidiabetic medications for type 2 diabetes (T2DM). Among the available oral medications, sodium-glucose cotransporters (SGLTs) are one class of medicine used to treat T2DM. Several SGLT2 inhibitors have been in the marketplace for years, while one combined SGLT1/SGLT2 inhibitor was recently approved by the Food and Drug Administration (FDA). Let’s take a more in-depth take a look at SGLT2 and SGLT1 inhibitors.

What do SGLT2 and SGLT1 do?

Glucose moves into and out of our cells using proteins divided into two classes: glucose transporters (GLUTs), which work through facilitated diffusion, and SGLTs, which actively transport glucose together with sodium into cells using a sodium concentration gradient (Sano, Shinozaki, & Ohta, 2020). Of the six various kinds of SGLT proteins within the body, two have been studied for his or her role in glucose absorption: SGLT1 works primarily within the small intestine, while SGLT2 works primarily within the kidneys.

The glomerulus filters about 180 grams of glucose per day, most of which is absorbed within the proximal tubule. SGLT2 is a high-capacity, low-affinity protein that helps absorb about 90-95% of glucose (160-180 g/d) within the S1 and S2 segments of the proximal tubule of the kidneys. SGLT1 is a low-capacity, high-affinity transporter that mediates about 5-10% of glucose absorption within the S3 (distal) segment of the proximal tubule and will help with additional glucose absorption by the kidneys. When blood glucose levels exceed the capability of the glucose cotransporters, excess glucose appears within the urine, which can indicate diabetes. SGLT1 can also be present in skeletal muscle and the guts, where it’s the first mediator of glucose absorption within the small intestine.

The following SGLTs have been approved by the FDA and are currently available in the marketplace (Facts and Comparisons, 2024b).

SGLT2 Inhibitors (DeSantis, 2024)

SGLT2 inhibitors help excrete glucose from the kidneys, lowering elevated blood glucose levels in patients with type 2 diabetes. SGLT2 inhibitors aren’t often used as initial therapy, but these drugs have been shown to be helpful in patients with cardiovascular and kidney disease. They are helpful in the next situations:

• In patients with atherosclerotic heart problems (CVD) or heart failure who cannot achieve glycemic goals with metformin and lifestyle changes
• To slow the decline in estimated glomerular filtration rate (eGFR) in patients with an eGFR lower than 90 ml/min/1.73 m²
• As a third-line agent in patients who fail to attain glycemic goals with two oral agents (i.e. metformin and a sulfonylurea) when metformin and insulin aren’t treatment options
• As a third-line agent in patients with inadequate glycemic control on metformin and insulin, in whom glucagon-like peptide-1 (GLP-1) receptor agonists are contraindicated and increasing the insulin dose would lead to weight gain
• As a second agent in patients with inadequate glycaemic control on metformin who’re unwilling or unable to contemplate injection therapy and who’re concerned about weight gain or risk of hypoglycaemia

SGLT2 inhibitors must be avoided for the treatment of hyperglycemia in patients with:

• Type 1 diabetes
• Type 2 diabetes and eGFR lower than 45 ml/min/1.73 m² (ertugliflozin) or lower than 30 ml/min/1.73 m² (empagliflozin, canagliflozin, dapagliflozin, bexagliflozin)
• History of diabetic ketoacidosis (DKA)

SGLT2 inhibitors must be used with caution in patients with:

• Frequent bacterial urinary tract infections or yeast infections of the genitourinary system
• Low bone density and high risk of falls, fractures and foot ulcers
• Predisposing aspects for ketoacidosis (i.e. pancreatic insufficiency, drug or alcohol use disorders, ketogenic diets)

Dual SGLT1/s inhibitors

Sotagliflozin (Inpefa) is a dual SGLT1/2 inhibitor approved by the FDA to scale back the danger of cardiovascular mortality and hospitalization for heart failure in adults with type 2 diabetes, chronic kidney disease, and other cardiovascular risk aspects (Facts and Comparisons, 2024a). Sotagliflozin has been studied as an adjunct therapy in type 1 diabetes. While phase III studies showed improvement in A1C tests at 24 weeks, the incidence of DKA was higher with sotagliflozin compared with placebo and is subsequently not beneficial as a treatment for type 1 diabetes (Weinstock, 2024).

Clinical Considerations (Desantis, 2024; Padda, Mahtani, & Parmar, 2023)

Before starting treatment with SGLT inhibitors, the patient must be assessed for:

• Volume status and risk of hypovolemia and hypotension
  • Hypovolemia must be corrected before starting therapy.
  • Adjust diuretics and blood pressure medications as needed

• Renal function – efficacy will decline with decreasing estimated glomerular filtration rate (eGFR)
  • Contraindicated in patients with end-stage renal disease or on dialysis
  • Dapagliflozin and ertugliflozin are contraindicated in case of eGFR lower than 60 ml/min
  • Canagliflozin and empagliflozin are contraindicated in case of eGFR lower than 45 ml/min

• Liver function before starting canagliflozin or dapagliflozin
• Bone density in patients exposed to falls and bone fractures
• Use of insulin or insulin secretagogues (sulfonylureas, glinides); insulin dose reduction to scale back the danger of hypoglycemia
• History of recurrent genital or urinary tract infections
• Neuropathy, foot deformity, vascular disease, and history of previous foot ulcers

• Monitor for symptoms of diabetic ketoacidosis (DKA); if suspected, evaluate and treat immediately.
• Monitor hydration status and renal function (serum creatinine and eGFR).
• Monitor for symptoms of genitourinary infections and foot ulcers.
• You should stop taking SGLT2 medicine about 3 to 4 days before a planned surgery.
• SGLT2 must be discontinued in case of severe illness or prolonged fasting.

Stay current with research as SGLT2 and SGLT1 inhibitors have the potential to positively impact clinical management and outcomes for patients with type 2 diabetes and other chronic diseases. For complete information, confer with the drug package insert or Nursing2024 Drug Handbook® + Drug Updates.

American Diabetes Association – Committee on Professional Practice (2024). 9. Pharmacologic Approaches to Glycemic Management: Standards of Care in Diabetes – 2024. (Supplement 1), S158–S178. https://doi.org/10.2337/dc24-S009

DeSantis, A. (2024, March 19). Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes. Retrieved from https://www.uptodate.com/contents/sodium-glucose-cotransporter-2-inhibitors-for-the-treatment-of-hyperglycemia-in-type-2-diabetes-mellitus

Facts and comparisons (2024a, February 26). Sotagliflozin Oral. Facts and comparisons. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/7346202?cesid=7DJZjAhjRd9

Facts and comparisons (2024b, January 31). Sodium-glucose cotransporter inhibitors 2. Facts and comparisons. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5545822?cesid=1tMly08RUaQ

Novak, L. M. and Kruger, D. F. (2017). Strengthening the arsenal with SGLT2 inhibitors. , (10), 28–34. https://doi.org/10.1097/01.NPR.0000524665.16846.63

Padda, I. S., Mahtani, A. U., and Parmar, M. (2023). Sodium glucose transport protein 2 (SGLT2) inhibitors. In . StatPearls Publishing.

Sano, R., Shinozaki, Y., and Ohta, T. (2020). Sodium-glucose cotransporters: functional properties and pharmaceutical potential. , (4), 770–782. https://doi.org/10.1111/jdi.13255

Weinstock, RS (2024, January 2). Blood glucose management in adults with type 1 diabetes. https://www.uptodate.com/contents/management-of-blood-glucose-in-adults-with-type-1-diabetes-mellitus

Zhao, M., Li, N., and Zhou, H. (2023). SGLT1: a possible drug goal for cardiovascular diseases. , , 2011–2023. https://doi.org/10.2147/DDDT.S418321